2007 Fiscal Year Final Research Report Summary
Establishment ofpredidive method for shift of coreceptor usage in HIV 1-infected individnals
| Project/Area Number |
18590533
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Kumamoto University |
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Principal Investigator |
MAEDA Yosuke Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Associate Professor (30284764)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Virus / Translational research / HIV / Coreceptor |
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| Research Abstract |
The disease progression of HIV-1 infection is largely associated with a switch of coreceptor usage by HIV-1 from CCR5 to CXCR4. Although most of CXCR4-using viruses retain CCR5 usage called R5X4 viruses, the replication of R5X4 viruses were inhibited by CXCR4 inhibitors alone in the cells expressing both CCR5 and CXCR4, indicating the preferential usage of CXCR4 by these viruses. In order to determine which regions of the Env are associated with the preferential usage of CXCR4, we isolated an escape mutant in the presence of a CXCR4 antagonist T140 from an R5X4 virus (89.6 strain). An isolated T140-escape mutant harbored a single amino acid substitution in the V3 region of gp120(Arginine to Serine, R308S). Luciferase-reporter HIV-1 pseudotyped with the mutant Env showed that the substitution totally conferred resistance to CXCR4 antagonists but increased sensitivity to a CCR5 antagonist TAK-779 in the infection of the cells expressing both CCR5 and CXCR4, indicating the preferential usage of CCR5. Analyses using the cells expressing a single coreceptor showed that the mutant Env predominantly and efficiently utilized CCR5 than CXCR4 with retaining R5X4 phenotype. These results indicated that the preferential usage of CXCR4 by the R5X4 virus was determined by the single amino acid in the V3 region of gp120.
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